Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical use of doxorubicin (Adriamycin), an antitumor agent, is limited by its oxyradical-mediated cardiotoxicity. We tested the hypothesis that moderate diet restriction protects against doxorubicin-induced cardiotoxicity by decreasing oxidative stress and inducing cardioprotective mechanisms. Male Sprague-Dawley rats (250-275 g) were maintained on diet restriction [35% less food than ad libitum]. Cardiotoxicity was estimated by measuring biomarkers of cardiotoxicity, cardiac function, lipid peroxidation, and histopathology. A LD(100) dose of doxorubicin (12 mg/kg, ip) administered on day 43 led to 100% mortality in ad libitum rats between 7 and 13 days due to higher cardiotoxicity and cardiac dysfunction, whereas all the diet restricted rats exhibited normal cardiac function and survived. Toxicokinetic analysis revealed equal accumulation of doxorubicin and doxorubicinol (toxic metabolite) in the ad libitum and diet restricted hearts. Mechanistic studies revealed that diet restricted rats were protected due to (1) lower oxyradical stress from increased cardiac antioxidants leading to downregulation of uncoupling proteins 2 and 3, (2) induction of cardiac peroxisome proliferators activated receptor-alpha and plasma adiponectin increased cardiac fatty acid oxidation (666.9+/-14.0 nmol/min/g heart in ad libitum versus 1035.6+/-32.3 nmol/min/g heart in diet restriction) and mitochondrial AMPalpha2 protein kinase. The changes led to 51% higher cardiac ATP levels (17.7+/-2.1 micromol/g heart in ad libitum versus 26.7+/-1.9 micromol/g heart in diet restriction), higher ATP/ADP ratio, and (3) increased cardiac erythropoietin and decreased suppressor of cytokine signaling 3, which upregulates cardioprotective JAK/STAT3 pathway. These findings collectively show that moderate diet restriction renders resiliency against doxorubicin cardiotoxicity by lowering oxidative stress, enhancing ATP synthesis, and inducing the JAK/STAT3 pathway.
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PMID:Mechanism of protection of moderately diet restricted rats against doxorubicin-induced acute cardiotoxicity. 1790 2

Transient reduction in coronary perfusion pressure in the isolated mouse heart increases microvascular resistance (paradoxical vasoconstriction) by an endothelium-mediated mechanism. To assess the presence and extent of paradoxical vasoconstriction in hearts from normal and diabetic rats and to determine whether increased heme oxygenase (HO)-1 expression and HO activity, using cobalt protoporphyrin (CoPP), attenuates coronary microvascular response, male Wistar rats were rendered diabetic with nicotinamide/streptozotocin for 2 wk and either CoPP or vehicle was administered by intraperitoneal injection weekly for 3 wk (0.5 mg/100 g body wt). The isolated beating nonworking heart was submitted to transient low perfusion pressure (20 mmHg), and coronary resistance (CR) was measured. During low perfusion pressure, CR increased and was associated with increased lactate release. In diabetic rats, CR was higher, HO-1 expression and endothelial nitric oxide synthase were downregulated, and inducible nitric oxide synthase and O(2)(-) were upregulated. After 3 wk of CoPP treatment, HO activity was significantly increased in the heart. Upregulation of HO-1 expression and HO activity by CoPP resulted in the abolition of paradoxical vasoconstriction and a reduction in oxidative ischemic damage. In addition, there was a marked increase in serum adiponectin. Elevated HO-1 expression was associated with increased expression of cardiac endothelial nitric oxide synthase, B-cell leukemia/lymphoma extra long, and phospho activator protein kinase levels and decreased levels of inducible nitric oxide synthase and malondialdehyde. These results suggest a critical role for HO-1 in microvascular tone control and myocardial protection during ischemia in both normal and mildly diabetic rats through the modulation of constitutive and inducible nitric oxide synthase expression and activity, and an increase in serum adiponectin.
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PMID:Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats. 1790 3

Adiponectin is a protein secreted from adipocytes that exhibits salutary effects in the vascular endothelium by signaling mechanisms that are not well understood. In obesity-related disease states and type 2 diabetes, circulating substances, including tumor necrosis factor-alpha (TNFalpha) and high glucose, activate IkappaB kinase (IKK)beta and reduce the abundance of its substrate, inhibitor of kappaB (IkappaB)alpha, leading to nuclear translocation of the transcription factor NF-kappaB and stimulation of an inflammatory signaling cascade closely associated with endothelial dysfunction. The present study demonstrates that the globular domain of adiponectin (gAd) potently suppresses the activation of IKKbeta by either TNFalpha or high glucose in human umbilical vein endothelial cells and ameliorates the associated loss of IkappaBalpha protein. Interestingly, activation of AMP kinase was substantially more effective than cAMP signaling in suppressing high glucose-induced IKKbeta activity, whereas both pathways were comparably active in suppressing the TNFalpha-induced increase in IKKbeta. Both cAMP/protein kinase A signaling and activation of the AMP kinase pathway played a role in the suppression by gAd of TNFalpha- and high glucose-mediated IKKbeta activation. These findings support an important role for adiponectin in anti-inflammatory signaling in the endothelium and also imply that multiple pathways are involved in the cellular effects of adiponectin.
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PMID:Adiponectin suppresses IkappaB kinase activation induced by tumor necrosis factor-alpha or high glucose in endothelial cells: role of cAMP and AMP kinase signaling. 1794 Feb 18

Mutation in PRKAG2 encoding the gamma2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic alpha- and regulatory beta-and gamma-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the gamma-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the gamma2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.
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PMID:[AMP-activated protein kinase: how a mistake in energy gauge causes glycogen storage]. 1799 Mar 92

In the light of recent studies in humans and rodents, AMP-activated protein kinase (AMPK), a phylogenetically conserved serine/threonine protein kinase, has been described as an integrator of regulatory signals monitoring systemic and cellular energy status. AMP-activated protein kinase (AMPK) has been proposed to function as a 'fuel gauge' to monitor cellular energy status in response to nutritional environmental variations. Recently, it has been proposed that AMPK could provide a link in metabolic defects underlying progression to the metabolic syndrome. AMPK is a heterotrimeric enzyme complex consisting of a catalytic subunit alpha and two regulatory subunits beta and gamma. AMPK is activated by rising AMP and falling ATP. AMP activates the system by binding to the gamma subunit that triggers phosphorylation of the catalytic alpha subunit by the upstream kinases LKB1 and CaMKKbeta (calmodulin-dependent protein kinase kinase). AMPK system is a regulator of energy balance that, once activated by low energy status, switches on ATP-producing catabolic pathways (such as fatty acid oxidation and glycolysis), and switches off ATP-consuming anabolic pathways (such as lipogenesis), both by short-term effect on phosphorylation of regulatory proteins and by long-term effect on gene expression. As well as acting at the level of the individual cell, the system also regulates food intake and energy expenditure at the whole body level, in particular by mediating the effects of insulin sensitizing adipokines leptin and adiponectin. AMPK is robustly activated during skeletal muscle contraction and myocardial ischaemia playing a role in glucose transport and fatty acid oxidation. In liver, activation of AMPK results in enhanced fatty acid oxidation as well as decreased glucose production. Moreover, the AMPK system is one of the probable targets for the anti-diabetic drugs biguanides and thiazolidinediones. Thus, the relationship between AMPK activation and beneficial metabolic effects provide the rationale for the development of new therapeutic strategies in metabolic disorders.
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PMID:Targeting AMP-activated protein kinase as a novel therapeutic approach for the treatment of metabolic disorders. 1799 41

Adiponectin, an adipokine predominantly secreted from adipose tissue, has potent anti-inflammatory properties. Although the mechanisms for the anti-inflammatory properties of adiponectin are not well understood, recent evidence suggests that increased production of interleukin-10 (IL-10), a potent immunomodulatory cytokine, is involved in the anti-inflammatory actions of adiponectin. Globular adiponectin (gAcrp) increased IL-10 promoter activity and IL-10 mRNA accumulation in RAW 264.7 macrophages. Deletion of the sequences from -416 and -369 in the IL-10 promoter, containing a cyclic AMP-response element (CRE), decreased gAcrp-induced IL-10 promoter activation. Treatment of RAW 264.7 macrophages with gAcrp increased the phosphorylation of cyclic AMP response element binding protein (CREB) at Ser(133), as well as enhanced the DNA binding activity of CREB. Further, overexpression of a dominant negative form of CREB suppressed gAcrp-induced transcriptional activation of IL-10. gAcrp-stimulated CREB phosphorylation was mediated by the activation of both ERK1/2- and cAMP-dependent protein kinase (PKA)-dependent pathways. Inhibition of either ERK1/2 or PKA activity prevented gAcrp-stimulated CREB phosphorylation, as well as gAcrp-stimulated IL-10 promoter activation. Taken together, these data identify gAcrp-stimulated phospho-CREB as a key transcription factor responsible for gAcrp-induced IL-10 promoter activation.
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PMID:Activation of cyclic-AMP response element binding protein contributes to adiponectin-stimulated interleukin-10 expression in RAW 264.7 macrophages. 1826 67

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a major role in maintaining energy homeostasis. Within individual cells, AMPK is activated by a rise in the AMP:ATP ratio that occurs following a fall in ATP levels. AMPK is also regulated by the adipokines, adiponectin and leptin, hormones that are secreted from adipocytes. Activation of AMPK requires phosphorylation of threonine 172 within the catalytic subunit by either LKB1 or calcium/calmodulin dependent protein kinase kinase beta (CaMKKbeta). AMPK regulates a wide range of metabolic pathways, including fatty acid oxidation, fatty acid synthesis, glycolysis and gluconeogenesis. In peripheral tissues, activation of AMPK leads to responses that are beneficial in counteracting the deleterious effects that arise in the metabolic syndrome. Recent studies have demonstrated that modulation of AMPK activity in the hypothalamus plays a role in feeding. A decrease in hypothalamic AMPK activity is associated with decreased feeding, whereas activation of AMPK leads to increased food intake. Furthermore, signalling pathways in the hypothalamus lead to changes in AMPK activity in peripheral tissues, such as skeletal muscle, via the sympathetic nervous system (SNS). AMPK, therefore, provides a mechanism for monitoring changes in energy metabolism within individual cells and at the level of the whole body.
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PMID:The role of the AMP-activated protein kinase in the regulation of energy homeostasis. 1826 75

Adipocytokines are a group of adipocyte-secreted proteins that have significant effects on the metabolism of lipids and carbohydrates, as well as numerous other processes. A number of recent studies have indicated that some adipocytokines may significantly influence the proliferation of malignant cells in vitro, whereas it remains unclear whether they have similar roles in vivo. In this study, we determined serum levels of adipocytokines in mice with azoxymethane (AOM)- and dextran sulfate sodium (DSS)-induced colon carcinogenesis. Five-week-old ICR mice were given a single intraperitoneal injection of AOM followed by 1% DSS in drinking water for 7 days. Nobiletin (NOB), a citrus flavonoid, was given in the diet (100 p.p.m) for 17 weeks. Thereafter, the incidence and number of colon tumors and serum concentration of adipocytokines were determined at the end of week 20. The serum leptin level in AOM/DSS-treated mice was six times higher than that in untreated mice, whereas there were no significant differences in the levels of triglycerides, adiponectin and interleukin-6. Feeding with NOB abolished colonic malignancy and notably decreased the serum leptin level by 75%. Further, NOB suppressed the leptin-dependent, but not independent, proliferation of HT-29 colon cancer cells and decreased leptin secretion through inactivation of mitogen-activated protein kinase/extracellular signaling-regulated protein kinase, but not that of adiponectin in differentiated 3T3-L1 mouse adipocytes in a dose-dependent manner. Taken together, our results suggest that higher levels of leptin in serum promote colon carcinogenesis in mice, whereas NOB has chemopreventive effects against colon carcinogenesis, partly through regulation of leptin levels.
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PMID:Suppressive effects of nobiletin on hyperleptinemia and colitis-related colon carcinogenesis in male ICR mice. 1837 60

Adiponectin is a fat-derived cytokine with anti-diabetic and anti-atherogenic properties. In this study, effects of sulfonylureas (SUs) on adiponectin production and the action mechanism were evaluated using 3T3-L1 adipocytes. The cells were incubated with glimepiride, glibenclamide, gliclazide, pioglitazone, metformin and the medium only as the control. In the control, the adiponectin level evaluated as the production rate per 24 h was not changed, while pioglitazone significantly increased the adiponectin level. SUs also increased the adiponectin level, but metformin failed to show any increase in adiponectin production. SUs induced adiponectin gene expression as well as pioglitazone. Pioglitazone significantly increased adipogenesis, but glimepiride did not. The aP2 gene expression was increased by pioglitazone, but not by glimepiride. Forskolin, a protein kinase A stimulator, reduced the adiponectin production stimulated by glimepiride but not by pioglitazone. These observations strongly suggest that SUs stimulate the adiponectin production through a different mechanism from pioglitazone, namely an interaction with protein kinase A activity. The significance of the extrapancreatic action of SUs observed in this study should be further evaluated in the clinical field.
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PMID:Effects of sulfonylurea drugs on adiponectin production from 3T3-L1 adipocytes: implication of different mechanism from pioglitazone. 1845 31

RKTG (Raf kinase trapping to Golgi) is exclusively localized at the Golgi apparatus and functions as a spatial regulator of Raf-1 kinase by sequestrating Raf-1 to the Golgi. Based on the structural similarity with adiponectin receptors, RKTG was predicted to be a seven-transmembrane protein with a cytosolic N-terminus, distinct from classical GPCRs (G-protein-coupled receptors). We analysed in detail the topology and functional domains of RKTG in this study. We determined that the N-terminus of RKTG is localized on the cytosolic side. Two short stretches of amino acid sequences at the membrane proximal to the N- and C-termini (amino acids 61-71 and 299-303 respectively) were indispensable for Golgi localization of RKTG, but were not required for the interaction with Raf-1. The three loops facing the cytosol between the transmembrane domains had different roles in Golgi localization and Raf-1 interaction. While the first cytosolic loop was only important for Golgi localization, the third cytosolic loop was necessary for both Golgi localization and Raf-1 sequestration. Taken together, these findings suggest that RKTG is a type III membrane protein with its N-terminus facing the cytosol and multiple sequences are responsible for its localization at the Golgi apparatus and Raf-1 interaction. As RKTG is the first discovered Golgi protein with seven transmembrane domains, the knowledge derived from this study would not only provide structural information about the protein, but also pave the way for future characterization of the unique functions of RKTG in the regulation of cell signalling.
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PMID:Characterization of the topology and functional domains of RKTG. 1854 65


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